Differential gear mechanism for a drug delivery device and drug delivery device

ABSTRACT

The invention is directed to a differential gear mechanism ( 26 ) for a drug delivery device with a primary drug delivery assembly ( 3 ) and a secondary drug delivery assembly ( 4 ), wherein the primary drug delivery assembly ( 3 ) comprises a primary dose dial sleeve ( 17 ) and wherein the secondary drug delivery assembly ( 4 ) comprises a secondary drive sleeve ( 24 ). The invention is also directed to a respective drug delivery device.

The present invention is directed to a differential gear mechanism for adrug delivery device with a primary drug delivery assembly and asecondary drug delivery assembly. The present invention is also directedto a drug delivery device comprising a respective differential gearmechanism.

Certain disease states require treatment using one or more differentmedicaments. Some drug compounds need to be delivered in a specificrelationship with each other in order to deliver the optimum therapeuticdose. Here, combination therapy may be desirable, but not possible in asingle formulation for reasons such as, but not limited to, stability,compromised therapeutic performance and toxicology.

For example, in some cases it might be beneficial to treat a diabeticwith a long acting insulin and with a glucagon-like peptide-1 (GLP-1),which is derived from the transcription product of the proglucagon gene.GLP-1 is found in the body and is secreted by the intestinal L cell as agut hormone. GLP-1 possesses several physiological properties that makeit (and its analogs) a subject of intensive investigation as a potentialtreatment of diabetes mellitus. Another example of a medicamentcombination is the administration of a pain reliever in combination witha medicament for treating osteoarthritis.

Drug delivery devices of the aforementioned kind often have applicationswhere regular injection by persons without formal medical trainingoccurs. This is increasingly common among patients having diabetes orthe like, e.g. osteoarthritis. Self-treatment enables such patients toconduct effective management of their disease.

In combination therapy, a primary medicament and a secondary medicamentare delivered in a specific relationship to deliver the optimumtherapeutic dose. The injection devices of the generic kind usuallycomprise a housing in which two or more drug delivery assemblies areretained. Such devices include a primary drug delivery assembly fordispensing the primary medicament such as the long-acting insulin and asecondary drug delivery assembly for dispensing the secondarymedicament, such as GLP-1. Some kinds of drug delivery assembliescomprise a compartment such as a cartridge holder for accommodating areplaceable medicament container such as a cartridge which stores themedicament.

In some cases, depending on the patient or the stage of the therapy, aneffective treatment requires variations in the quantities and/orproportions of the medicaments making up the combined therapy. Forexample, the patient may require a non-adjustable fixed dose of thesecondary medicament in combination with an adjustable variable dose ofthe primary medicament.

The effectiveness of a combined delivery of medicaments may require oneor more doses to be delivered sequentially with one of the twomedicaments being injected into the human body prior to the delivery ofthe other medicament. Such treatment may be conducted with devices thatinclude two separate dispensing mechanisms that are actuatedindependently from each other such that the dispensing mechanisms areactivated successively. This, however, may be hazardous for patientsthat are physically or mentally impaired or otherwise disadvantaged. Itis desirable to have a device that is provided with merely one dispensebutton respectively an actuator which the patient can trigger and whichleads to a sequential delivery of the primary and the secondarymedicament.

It is an object of the invention to improve the setting and dispensecapabilities of a drug delivery device of the aforementioned kind.Further, it is desired to enable the user to choose either to dispense adose of only one the medicaments or a combined dose of both medicaments.

The above problem is solved by a differential gear mechanism for a drugdelivery device as defined in claim 1 and a drug delivery device asdefined in claim 4.

The drug delivery devices of the aforementioned kind comprise a primarydrug delivery assembly with a primary dose dial sleeve and a secondarydrug delivery assembly with a secondary drive sleeve. The differentialgear mechanism comprises a first toothing, a transmission elementmovable relative to the first toothing in a first axial direction andcomprising at least one first gear wheel and at least one second gearwheel concentrically arranged with respect to the first gear wheel.Further, a second toothing that is configured to be axially constrainedto the primary dose dial sleeve and a third toothing that is configuredto the axially constrained to the secondary drive sleeve and a fourthtoothing are provided. The second toothing, the third toothing and thefourth toothing are movable relative to the first toothing in axialdirection. The first gear wheel is in meshed engagement with the firsttoothing and the fourth toothing while the second gear wheel is inmeshed engagement with the second toothing and the third toothing. Thefirst toothing may be arranged stationary at least in axial directionwith respect to the second, third and fourth toothing.

Preferably, the dose dial sleeve comprises a number of indices forvisually indicating the set dose. Accordingly, in the following, theprimary dose dial sleeve is referred to as the primary number sleeve.

The differential gear mechanism enables for a drug delivery device wherea user can choose whether he only wishes to set and dispense a dose of aprimary medicament contained in the primary drug delivery device or toset and dispense a dose of the primary medicament in combination with aset dose of a second medicament in the secondary drug delivery assembly.The implementation of this mechanism delivers a very precise setting anddelivery of medicament doses. For example, the differential gearmechanism can be used in combination with a drug delivery device whichis configured to dispense a variable dose of a primary medicament and asecondary drug delivery assembly which is configured for the delivery ofa fixed dose of a secondary medicament. The user has optimal conditionsfor combined therapy treatment. Further, the invention provides forimproved dispensing properties, e.g. by operating a common dose dispensebutton.

The term “fixed dose” as used herein can be characterized as a dosevalue that is defined by the construction of the drug delivery assembly,wherein the user is only able to inject a specific dose. The user is notin the position to set lower or higher doses of medicament and/or toinject lower or higher doses of the medicament. The dose the user mayeffectively set and inject is restricted to a certain value.

On the contrary, the term “variable dose” can be characterized as a dosewhere the user is substantially free to choose the amount of medicamenthe wants to inject. The dose is variably adjustable, normally betweenupper and lower limits.

The transmission element may comprise at least one or more first andsecond gear wheels respectively.

According to the second embodiment of the invention, the fourth toothingis movable relative to the second toothing in axial direction. Thefourth toothing may be movable relative to the second toothing between afirst relative position and a second relative position in axialdirection. This enables for the convenient individual setting of thesecondary drug delivery assembly without affecting a dose setting in theprimary drug delivery assembly. Further, it enables for the effectivesetting of a fixed dose in a secondary drug delivery assembly.

Preferably, each of the toothings is formed as a gear rack with a numberof teeth arranged side by side, the arrangement preferably extending inaxial direction.

A further embodiment of the invention concerns a differential gearmechanism for a drug delivery device with a primary drug deliveryassembly comprising a primary dose dial sleeve configured to moveproximally in a helical movement during setting of a dose of a primarymedicament contained in a primary reservoir of the primary drug deliveryassembly, and with a secondary drug delivery assembly comprising asecondary drive sleeve configured to move in a proximal direction in ahelical movement during setting of a dose of a secondary medicamentcontained in a secondary reservoir of the secondary drug deliveryassembly; the differential gear mechanism comprising a first toothing; atransmission element movable relative to the first toothing in a firstaxial direction and comprising at least one first gear wheel and atleast one second gear wheel concentrically arranged with respect to thefirst gear wheel; a second toothing axially constrained to the primarydose dial sleeve; a third toothing axially constrained to the secondarydrive sleeve; and a fourth toothing. The second toothing, the thirdtoothing and the fourth toothing are moveable relative to the firsttoothing in the first axial direction and the fourth toothing is movablerelative to the second toothing in the axial direction; and the firstgear wheel is in meshed engagement with the first toothing and thefourth toothing; and the second gear wheel is in meshed engagement withthe second toothing and third toothing such that when the secondarydrive sleeve moves proximally, axial motion of the third toothing causesrelative axial movement between the second toothing and the fourthtoothing, and such that when the primary dose dial sleeve movesproximally motion of the second toothing in proximal direction causesthe second toothing and the forth toothing to move together in proximaldirection.

In this regard, it is preferred when the first toothing is arrangedstationary with respect to the housing.

The above embodiment provides for a clear indication mechanism whether adose of the secondary medicament in the secondary drug delivery assemblyhas been set or not. Setting the dose of the primary medicament, whichis connected with proximal displacement of the primary dose dial sleeve,does not cause said relative displacement so that the user can get aclear indication that he is about to inject a dose of the primarymedicament only. The relative displacement between the second toothingand the forth toothing, which takes place when the secondary drivesleeve is moved proximally when the dose of the secondary medicament isset, can be effectively used to implement a common actuation mechanism.In this regard, whether or not the primary dose dial sleeve or thesecondary drive sleeve rotate during dose setting is not important asthe differential gear mechanism merely depends on the axial displacementof the primary dose dial sleeve or the secondary drive sleeve during thesetting of a dose of the primary or the secondary medicament.

The object of the invention is also solved by drug delivery devicecomprising a primary drug delivery assembly with a primary dose dialsleeve and a secondary drug delivery assembly with a secondary drivesleeve and a differential gear mechanism as described herein, whereinthe first toothing is fixed stationary with respect to a drug deliveryhousing, wherein the second toothing axially constrained to the primarydose dial sleeve, and wherein the third toothing is axially constrainedto the secondary drive sleeve.

The implementation of the differential gear mechanism enables for aprecise coupling of the drug delivery assembly. In particular, thefourth toothing may be efficiently used for indication that a dose inthe secondary drug delivery assembly is set.

Preferably, the secondary drive sleeve is configured to move proximallyin a helical movement during dose setting and to move distally in a pureaxial motion during dose dispense. A helical movement can becharacterized as a movement of combination of a longitudinal motion incombination with a rotation about the axis of motion.

Preferably, the primary number sleeve is configured to move proximally ahelical movement during dose setting and to move distally in theopposite direction in an opposite helical movement during dose dispense.

The drug delivery housing may extend from a proximal end to a distal endalong a first longitudinal axis and accommodates the primary and thesecondary drug delivery assembly. The distal end is usually referred toas the dispensing end, where the drug delivery device may be equippedwith a single dispense interface, such as an injection needle. Theproximal end is usually referred to as the actuation end, where a userpresses a button or the like to start injection.

The drug delivery device may comprise a movable element movable withrespect to the primary dose dial sleeve between a first e.g. distalposition, and a second position, e.g. proximal position. The fourthtoothing may engage the movable element when the secondary drive sleeveis moved in proximal direction, resp. when the dose of the secondarymedicament is set, e.g. by rotating the secondary drive sleeve in ahelical movement in proximal direction such that movement of thirdtoothing is transferred though the differential gear mechanism to thefourth toothing in proximal direction and to the movable element.Herewith, the actuation mechanisms are efficiently coupled and a clearindication that a dose of medicament in the secondary drug deliveryassembly has been set can be provided.

The primary drug delivery assembly may be retained in or attached to thedrug delivery device housing and may be configured such as to deliver avariable dose of a first medicament and the secondary drug deliveryassembly may be retained in or attached to the drug delivery devicehousing and may be configured to deliver only a fixed dose of a secondmedicament. The primary and secondary drug delivery assembly may eachcontain a medicament reservoir. A primary medicament, e.g. a long-actinginsulin may be contained in the primary reservoir and a secondarymedicament, e.g. GLP-1, may be contained in the secondary reservoir.

The primary drug delivery assembly may comprise a primary dose settingmechanism and a primary dose dispense mechanism. The secondary drugdelivery assembly may comprise a secondary dose setting mechanism and asecondary dose dispense mechanism. The drug delivery device may includea variable dose setting mechanism which is associated with the primarydrug delivery assembly to set a variable dose of the primary medicamentand a fixed dose setting mechanism which is associated with thesecondary drug delivery assembly to set a fixed dose of the secondarymedicament. The primary drug delivery assembly and the secondary drugdelivery assembly may each extend along a longitudinal axis, which runspreferably parallel to the longitudinal axis of the housing

The primary drug delivery assembly may include a primary drug deliveryassembly housing. Alternatively, the housing of the drug delivery devicemay constitute the primary drug delivery assembly housing. The secondarydrug delivery assembly may include a secondary drug delivery assemblyhousing. Alternatively, the housing of the drug delivery device mayconstitute the secondary drug delivery assembly housing.

The primary drug delivery assembly may further comprise an actuationelement such as a dose setter or a dose dial grip configured to berotationally fixed to the number sleeve during dose setting such thatrotation of the actuation element causes the number sleeve to rotate andto wind out of the housing in a combination of translational androtational movement.

The movable element may be a dispense button or the like with anabutment surface arranged proximally from an engagement section orabutment surface of the fourth toothing so that movement of the fourthtoothing in proximal direction causes engagement with the button andaxial movement of the fourth toothing is transferred to the movableelement. For example, the fourth toothing may formed as a gear rack witha proximally oriented engagement section which abuts a distally orientedengagement section of the dispense button such that fourth toothingmoves the dispense button proximally with respect to a dose dial gripand a proximal surface of the dispense button projects or protrudes froma proximal end of the dose dial grip.

The first toothing may be arranged stationary at least in axialdirection with respect to the second, third and fourth toothing by beingprovided, e.g. formed, on the secondary drug delivery assembly housingor a housing element of the secondary drug delivery assembly.Alternatively, the first toothing may be fixed stationary within thedrug delivery housing. Preferably, the first toothing is formed as agear rack

The second toothing may be axially constrained to the primary numbersleeve by being connected or coupled to the primary number sleeve suchthat movement of the primary number sleeve in axial direction istransferred to the second toothing. The second toothing may be formed asan elongated gear rack extending in axial direction and arrangedparallel to the primary number sleeve. The second toothing may becoupled to the primary number sleeve such that relative rotation betweenthe primary number sleeve and the second toothing is possible butrelative axial movement is prevented. Alternatively, the second toothingmay be connected or coupled to the primary number sleeve by engaging adosing element such as an actuation element, which is rotationallycoupled to the primary number sleeve during dose setting, such thatrelative rotation between the primary number sleeve or the actuationelement and the second toothing is possible but relative axial movementis prevented. For example, the second toothing may comprise a collar orthe like engaging a groove on the outer surface of the primary numbersleeve or the actuation element. The second toothing may be axiallyguided by the housing, e.g. by means of axially extending guidancegrooves in the housing engaged by a projection on the second toothing toform a splined connection or the like.

The third toothing is axially constrained to the secondary drive sleeve.For this purpose, the third toothing may comprise a pin, a projection orthe like engaging a circumferential recess or the like on the secondarydrive sleeve such the third toothing and the secondary drive sleeve arecoupled for mutual movement in axial direction while relative rotationalmovement is allowed. The third toothing may be axially guided by thehousing, e.g. by means of guidance grooves or the like. Preferably, thethird toothing is formed as a gear rack

The fourth toothing may be constrained to slide axially relative to thesecond toothing. Preferably it is formed as a gear rack extending inaxial direction. The fourth toothing may be formed as part of a sleevearranged radially inwardly with respect to the second toothing which mayalso be formed as part of a sleeve. The fourth toothing may be axiallyguided by the second toothing such that relative rotation is preventedbut relative axial movement is possible. For that purpose, guidancemeans such as guidance grooves or the like can be formed on the innersurface of the second toothing and engage an outer surface of the fourthtoothing. The fourth toothing and the second toothing may be adapted toeach other such that motion of fourth toothing in the distal directionrelative to the second toothing is limited by an abutment against thesecond toothing, at which point the fourth toothing and the secondtoothing become fixed relative to each other in distal direction.Relative motion of the fourth toothing in proximal direction maygenerate an abutment with the movable element. Additional relativemotion in proximal direction may cause the moveable element to moverelative to the second toothing, the primary number sleeve, the drugdelivery housing and a dose dial grip.

The transmission element may be formed as or comprise a gear shaft withthe first gear wheel and the second gear wheel arranged on the shaftcomparable to a gear shaft. The first gear wheel may be rotationallyfixed to or formed on the shaft. The second gear wheel may berotationally supported by the shaft such that relative rotation betweenthe first gear wheel and the second gear wheel is possible. Thetransmission element is constrained to move axially relative to thehousing of the drug delivery device, resp. the first toothing. This maybe achieved by the meshed engagement of the gear wheels with therespective toothing.

According to a further embodiment of the invention, the primary numbersleeve is configured to move proximally a helical movement during dosesetting and to move distally in the opposite direction in an oppositehelical movement during dose dispense. The actuation element may beaxially constrained with respect to the second toothing at least duringmovement of the actuation element in distal direction but free to rotaterelative to the second toothing such that during dose setting of theprimary drug delivery assembly, the actuation element moves in proximaldirection which efficiently indicates that a dose of the primarymedicament is set. Accordingly, when the actuation element is moved indistal direction, this axial movement is transferred to the primarynumber sleeve. The actuation element may at least partly accommodate themovable element. The primary number sleeve may comprise a groove whichis formed in a helical pattern on its outer surface in axial directionand the housing of the drug delivery device or of the primary drugdelivery assembly may comprise a projection or the like engaging thegroove such that rotation of the number sleeve forces the number sleeveto move axially as well. The second toothing may comprises a collar orthe like engaging a recess on the actuation element such that axialmotion in proximal direction is directly transferred to the secondtoothing. Alternatively, second toothing may comprises a collar or thelike engaging a recess on the number sleeve such that axial motion ofthe number sleeve in proximal direction is directly transferred to thesecond toothing.

According to a further embodiment, the movable element is configured tomove the fourth toothing in distal direction when moved from the secondposition into the first position. This enables for the direct dispenseof a set dose of the secondary medicament in the secondary drug deliveryassembly prior to the dispense of the primary medicament. The fourthtoothing may engage the dispense button of the drug delivery device whenmoved in proximal direction such that the dispense button is moved fromits first proximal position into its second distal position. By movingthe dispense button back into the first proximal position, the movementis transferred to the fourth toothing and through the differential gearmechanism to the third toothing which is axially constrained to thesecondary drive sleeve so that axial movement is transferred tosecondary drive sleeve which is moved in distal direction such that thesecondary medicament is dispensed.

According to a further embodiment, the movable element is moveablerelative to the actuation element in axial direction, preferably betweenits first, e.g. distal, position and its second, e.g. proximal,position, wherein when the actuation element is moved from its secondposition to its first position, the movable element engages theactuation element such that further movement of the moveable element indistal direction is transferred to the actuation element. This enablesfor an effective sequential delivery of secondary and primarymedicament. When the movable element is moved from its proximal positiontowards its distal position, the displacement is transferred to thefourth toothing and through the differential gear mechanism to thesecondary drive sleeve. When the movable element reaches the secondposition further axial movement is transferred to the actuation element.

It is preferred, when at least one of the cartridges of the drugdelivery device is filled with the medicament. Also, the drug deliverydevice can be a disposable injection device. Such devices can be thrownaway or recycled after the content of the medicament has been exhausted.However, the present invention is also applicable with re-usable devicesdesigned to replace an emptied cartridge with a filled one after thewhole content of the former cartridge has been administered.

The term “medicament”, as used herein, means a pharmaceuticalformulation containing at least one pharmaceutically active compound,wherein in one embodiment the pharmaceutically active compound has amolecular weight up to 1500 Da and/or is a peptide, a proteine, apolysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or afragment thereof, a hormone or an oligonucleotide, or a mixture of theabove-mentioned pharmaceutically active compound,

wherein in a further embodiment the pharmaceutically active compound isuseful for the treatment and/or prophylaxis of diabetes mellitus orcomplications associated with diabetes mellitus such as diabeticretinopathy, thromboembolism disorders such as deep vein or pulmonarythromboembolism, acute coronary syndrome (ACS), angina, myocardialinfarction, cancer, macular degeneration, inflammation, hay fever,atherosclerosis and/or rheumatoid arthritis,

wherein in a further embodiment the pharmaceutically active compoundcomprises at least one peptide for the treatment and/or prophylaxis ofdiabetes mellitus or complications associated with diabetes mellitussuch as diabetic retinopathy, wherein in a further embodiment thepharmaceutically active compound comprises at least one human insulin ora human insulin analogue or derivative, glucagon-like peptide (GLP-1) oran analogue or derivative thereof, or exendin-3 or exendin-4 or ananalogue or derivative of exendin-3 or exendin-4.

Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) humaninsulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) humaninsulin; Asp(B28) human insulin; human insulin, wherein proline inposition B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein inposition B29 Lys may be replaced by Pro; Ala(B26) human insulin;Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) humaninsulin.

Insulin derivates are for example B29-N-myristoyl-des(B30) humaninsulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl humaninsulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin;B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30human insulin; B29-N—(N-palmitoyl-Y-glutamyl)-des(B30) human insulin;B29-N—(N-lithocholyl-Y-glutamyl)-des(B30) human insulin;B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin andB29-N-(ω-carboxyhepta-decanoyl) human insulin.

Exendin-4 for example means Exendin-4(1-39), a peptide of the sequenceH-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.

Exendin-4 derivatives are for example selected from the following listof compounds:

H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,

H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,

des Pro36 Exendin-4(1-39),

des Pro36 [Asp28] Exendin-4(1-39),

des Pro36 [IsoAsp28] Exendin-4(1-39),

des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),

des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),

des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),

des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),

des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),

des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or

des Pro36 [Asp28] Exendin-4(1-39),

des Pro36 [IsoAsp28] Exendin-4(1-39),

des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),

des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),

des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),

des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),

des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),

des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),

wherein the group -Lys6-NH2 may be bound to the C-terminus of theExendin-4 derivative;

or an Exendin-4 derivative of the sequence

des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010),

H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,

des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,

H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,

H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,

des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,

H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,

H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]Exendin-4(1-39)-NH2,

des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]Exendin-4(1-39)-(Lys)6-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]Exendin-4(1-39)-(Lys)6-NH2,

H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,

des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,

H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]Exendin-4(1-39)-NH2,

des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]Exendin-4(1-39)-(Lys)6-NH2,

H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28]Exendin-4(1-39)-(Lys)6-NH2,

H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,

H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25]Exendin-4(1-39)-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]Exendin-4(1-39)-NH2,

des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]Exendin-4(1-39)-(Lys)6-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]Exendin-4(S1-39)-(Lys)6-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]Exendin-4(1-39)-(Lys)6-NH2;

or a pharmaceutically acceptable salt or solvate of any one of theafore-mentioned Exendin-4 derivative.

Hormones are for example hypophysis hormones or hypothalamus hormones orregulatory active peptides and their antagonists as listed in RoteListe, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin,Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin),Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin,Buserelin, Nafarelin, Goserelin.

A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid,a heparin, a low molecular weight heparin or an ultra low molecularweight heparin or a derivative thereof, or a sulphated, e.g. apoly-sulphated form of the above-mentioned polysaccharides, and/or apharmaceutically acceptable salt thereof. An example of apharmaceutically acceptable salt of a poly-sulphated low molecularweight heparin is enoxaparin sodium.

Antibodies are globular plasma proteins (˜150 kDa) that are also knownas immunoglobulins which share a basic structure. As they have sugarchains added to amino acid residues, they are glycoproteins. The basicfunctional unit of each antibody is an immunoglobulin (Ig) monomer(containing only one Ig unit); secreted antibodies can also be dimericwith two Ig units as with IgA, tetrameric with four Ig units liketeleost fish IgM, or pentameric with five Ig units, like mammalian IgM.

The Ig monomer is a “Y”-shaped molecule that consists of fourpolypeptide chains; two identical heavy chains and two identical lightchains connected by disulfide bonds between cysteine residues. Eachheavy chain is about 440 amino acids long; each light chain is about 220amino acids long. Heavy and light chains each contain intrachaindisulfide bonds which stabilize their folding. Each chain is composed ofstructural domains called Ig domains. These domains contain about 70-110amino acids and are classified into different categories (for example,variable or V, and constant or C) according to their size and function.They have a characteristic immunoglobulin fold in which two β sheetscreate a “sandwich” shape, held together by interactions betweenconserved cysteines and other charged amino acids.

There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ,and μ. The type of heavy chain present defines the isotype of antibody;these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies,respectively.

Distinct heavy chains differ in size and composition; α and γ containapproximately 450 amino acids and δ approximately 500 amino acids, whileμ and ε have approximately 550 amino acids. Each heavy chain has tworegions, the constant region (C_(H)) and the variable region (V_(H)). Inone species, the constant region is essentially identical in allantibodies of the same isotype, but differs in antibodies of differentisotypes. Heavy chains γ, α and δ have a constant region composed ofthree tandem Ig domains, and a hinge region for added flexibility; heavychains μ and ε have a constant region composed of four immunoglobulindomains. The variable region of the heavy chain differs in antibodiesproduced by different B cells, but is the same for all antibodiesproduced by a single B cell or B cell clone. The variable region of eachheavy chain is approximately 110 amino acids long and is composed of asingle Ig domain.

In mammals, there are two types of immunoglobulin light chain denoted byA and K. A light chain has two successive domains: one constant domain(CL) and one variable domain (VL). The approximate length of a lightchain is 211 to 217 amino acids. Each antibody contains two light chainsthat are always identical; only one type of light chain, K or A, ispresent per antibody in mammals.

Although the general structure of all antibodies is very similar, theunique property of a given antibody is determined by the variable (V)regions, as detailed above. More specifically, variable loops, threeeach the light (VL) and three on the heavy (VH) chain, are responsiblefor binding to the antigen, i.e. for its antigen specificity. Theseloops are referred to as the Complementarity Determining Regions (CDRs).Because CDRs from both VH and VL domains contribute to theantigen-binding site, it is the combination of the heavy and the lightchains, and not either alone, that determines the final antigenspecificity.

An “antibody fragment” contains at least one antigen binding fragment asdefined above, and exhibits essentially the same function andspecificity as the complete antibody of which the fragment is derivedfrom. Limited proteolytic digestion with papain cleaves the Ig prototypeinto three fragments. Two identical amino terminal fragments, eachcontaining one entire L chain and about half an H chain, are the antigenbinding fragments (Fab). The third fragment, similar in size butcontaining the carboxyl terminal half of both heavy chains with theirinterchain disulfide bond, is the crystalizable fragment (Fc). The Fccontains carbohydrates, complement-binding, and FcR-binding sites.Limited pepsin digestion yields a single F(ab′)2 fragment containingboth Fab pieces and the hinge region, including the H—H interchaindisulfide bond. F(ab′)2 is divalent for antigen binding. The disulfidebond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, thevariable regions of the heavy and light chains can be fused together toform a single chain variable fragment (scFv).

Pharmaceutically acceptable salts are for example acid addition saltsand basic salts. Acid addition salts are e.g. HCl or HBr salts. Basicsalts are e.g. salts having a cation selected from alkali or alkaline,e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), whereinR1 to R4 independently of each other mean: hydrogen, an optionallysubstituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenylgroup, an optionally substituted C6-C10-aryl group, or an optionallysubstituted C6-C10-heteroaryl group. Further examples ofpharmaceutically acceptable salts are described in “Remington'sPharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), MarkPublishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia ofPharmaceutical Technology.

Pharmaceutically acceptable solvates are for example hydrates.

Exemplary embodiments of the invention will now be described withreference to the accompanying drawings, in which:

FIG. 1: shows in perspective sectional view, a drug delivery device inaccordance with the present invention;

FIG. 2: shows a perspective view of the components of the differentialgear mechanism;

FIG. 3: shows a sectional view of a part of the drug delivery device;

FIG. 4: shows another sectional view of a part of the drug deliverydevice;

FIG. 5: shows a perspective view of the number sleeve;

FIG. 6: shows a perspective view of the third gear rack;

FIG. 7: shows a perspective view the selection switch assembly

FIG. 8: shows a perspective view part of the secondary drug deliveryassembly;

FIG. 9: shows a sectional view another part of the drug delivery device;

FIG. 10: shows a sectional view a further part of the drug deliverydevice;

FIG. 11a-c : show the elements of FIG. 10 in different conditions;

FIG. 12: shows the element of FIG. 10 in a further condition;

FIG. 13: shows in a sectional view a further part of the drug deliverydevice in accordance with a further embodiment of the invention;

FIG. 14: shows the elements of FIG. 13 in a further condition;

FIG. 15: shows a drug delivery device in accordance with a furtherembodiment of the invention;

FIG. 16a, b : show different housing parts of the drug delivery deviceof FIG. 15.

The drug delivery device 1 comprises a housing 2 in which a primary drugdelivery assembly 3 and a secondary drug delivery assembly 4 areretained. The housing 2 extends along a longitudinal axis 5 from aproximal end 6 to a distal end 7 of the drug delivery device 1. Aprimary reservoir 8 (medicament cartridge) is arranged in the primarydrug delivery assembly 3 at its distal end. A secondary reservoir 9(medicament cartridge) is arranged in the secondary drug deliveryassembly 4 at its distal end. Each of the cartridges 8 and 9 is sealedat its distal end by a septum 10. A single dispense interface (notshown) with a single injection needle can be attached to the distal end7 of the drug delivery device housing 2, the single dispense interfacehaving two proximal needles, each of the needles piercing through one ofthe septa 10 so that a primary medicament 11 in the primary reservoir 8and a secondary medicament 12 in the secondary reservoir 9 can bedispensed through the single dispense interface through the injectionneedle.

At the proximal end of the primary cartridge 8, a bung 13 is providedand at the proximal end of the secondary cartridge 9, a bung 14 isprovided. When the single dispense interface is properly attached to thedrug delivery device 1 and the bungs 13 and 14 are moved in distaldirection, the medicaments 11 and 12 are forced out of the respectivereservoir 8, 9 through the single dispense interface.

The primary drug delivery assembly 3 comprises a variable dose settingand dose dispensing mechanism 15 and the secondary drug deliveryassembly 4 comprises a fixed dose setting and dispense mechanism 16.

The variable dose setting and dispense mechanism 15 includes a numbersleeve (dosing sleeve) 17, a primary drive sleeve 18, a lead screw 19,an inner body 20, a last dose nut 21 and a dial grip 22 (actuationelement). The inner body 20 is fixed relative to the housing 2.

The fixed dose mechanism 16 includes a secondary lead screw 23, asecondary drive sleeve 24 and a fixed dose mechanism housing 25. Adifferential gear mechanism 26 connects the variable dose setting anddispense mechanism 15 and the fixed dose setting and dispense mechanism16.

When the dose dial grip 22 is rotated about an axis extending from theproximal end to the distal end of the primary drug delivery assembly 3to set or dial a dose, the dose dial grip 22 is rotationally fixed tothe primary number sleeve 17 by means of a clutch (not shown). Thenumber sleeve 17 is in threaded engagement with the inner body 20 via ahelical thread such that upon rotation of the dose dial grip 22, thenumber sleeve 17 is constrained to move relative to the inner body 20along a helical path. During dose setting, resp. dose dialing, thenumber sleeve 17 winds out of the inner body 20 in proximal direction.

The primary drive sleeve 18 is a tubular element having differentdiameter regions and is rotationally locked to the dial grip 22. Theprimary lead screw 19 is an elongated element with an outer surface 27having two external threads 28, 29 with opposite hands which overlapeach other. The distal region of the primary drive sleeve 18 has aninner thread or projection 32 that engages one of the external threads28, 29 of the lead screw 19. One of the threads 28, 29 engages an innerthread resp. projection 30 of the inner body 20. A disc-like bearing 31is provided at the distal end of the lead screw 19. A moveable button 33is provided at the proximal end of the housing 2.

During dose setting, the dial grip 22, the number sleeve 17 and theprimary drive sleeve 18 are rotationally and axially locked by a clutchmechanism (not shown). Clockwise rotation of the dial grip 22 causes theprimary drive sleeve 18 to rotate and in doing so, it advances along thelead screw 19 which remains fixed throughout dialing.

When the desired dose is dialed, the dial grip 22 can be depressed indistal direction. Dial grip 22, primary drive sleeve 18 and inner body20 are rotationally locked, while dial grip 22, primary drive sleeve 18and number sleeve 17 are axially coupled. The rotational constraintbetween the dial grip 22 and number sleeve 17 is removed as a result ofa small relative axial displacement between them. The dial grip 22, theinner body 20 and primary drive sleeve 18 are rotationally locked. Asthe dial grip 22 is depressed via the button 33, the primary numbersleeve 17 moves along its helical path relative to the inner body 20 indistal direction and the dial grip 22 moves axially with the numbersleeve 17 but does not rotate due to its rotational constrain to theinner body 20. Axial movement of the drive sleeve 18 results in theprimary lead screw 19 to be driven forward to the dispense drug from thecartridge 8.

In the fixed dose mechanism 16, the secondary drive sleeve 24 isconstrained to move relative to the housing 25 along a pre-defined path.The secondary drive sleeve 24 consists of helical segments, alternatingwith pure axial segments to return the secondary drive sleeve 24 and thefixed dose mechanism housing 25 to the same relative axial position.

During setting of the fixed dose, the secondary drive sleeve 24 movesrelative to the housing 25 along a helical path in proximal direction.Once the secondary drive sleeve 24 has reached the end of the helicalsegment, a fixed dose is set. For dispense, the drive sleeve 24 is movedforward in a pure axial motion in distal direction to deliver the fixeddose. Inner helical segments on the secondary drive sleeve 24 arematched to an outer helical track 34 on the secondary lead screw 23. Thesecondary lead screw 23 remains stationary during helical motion of thedrive sleeve 24 in proximal direction. Axial motion of the secondarydrive sleeve 24 causes the secondary lead screw 23 to advance towardsthe distal end. The bung 14 in the secondary cartridge is moved indistal direction so that the secondary medicament is dispensed.

The dose setting and dose dispense elements of the primary drug deliveryassembly 3 and the secondary drug delivery assembly 4 are linked by thedifferential gear mechanism 26, its components being displayed in FIG. 2in an explosive view. The differential gear mechanism comprises a firsttoothing (first gear rack) 35 provided on the fixed dose mechanismhousing 25, a second toothing (second gear rack) 36, a third toothing(third gear rack) 37 and a firth toothing (fourth gear rack) 38.Further, a transmission element 39 comprising a first gear wheel 40 andtwo second gear wheels 41 that are concentrically arranged such that afirst gear wheel 40 and the second gear wheels 41 rotate along a commonaxis of rotation.

The first gear rack 35 is formed on the outside of the fixed dosemechanism housing 25 and also has a gear rack extending in axialdirection of the drug delivery device.

The second gear rack 36 is an elongated element having a gear rack atits distal (here left side) end, the gear rack consisting of two sets oftoothings respectively arranged side by side in a direction from thedistal end of the housing towards the proximal end of the housing. Theproximal end of the second gear rack 36 is configured to be axiallyconstrained with respect to the primary number sleeve and has asleeve-like proximal end section 42. The housing 2 is formed such thatthe second gear 36 rack is axially guided and is prevented fromrotating. The second gear rack may be referred to as the “variable doserack”.

The third gear rack 37 is axially constrained to the secondary drivesleeve 24. It is further accommodated in the housing 2 such thatrelative rotation with respect to the housing 2 is prevented. The thirdgear rack 37 may only slide in axial direction of the housing 2. Thehousing 2 is formed such that the third gear rack 37 is axially guidedand is prevented from rotating.

The fourth gear rack 38 is constrained to slide axially relative to thesecond gear rack 36. The fourth gear rack 38 is formed as part of asleeve arranged radially inwardly with respect to the second gear rack36, which is also formed as part of a sleeve. The fourth gear rack 38 isaxially guided by the second gear rack 36 such that relative rotation isprevented but relative axial movement is possible. Motion of the fourthgear rack 38 relative to the second gear rack 36 in distal direction islimited by an abutment on the inner surface of the sleeve section of thesecond gear rack 36.

The transmission element 39 comprises a shaft on which the first gearwheel 40 is formed. The second gear wheels 41 are rotationally supportedby the shaft and concentrically arranged with respect to the first gearwheel 40 such that the first gear wheel 40 and the second gear wheels 41share a common rotational axis. The first gear wheel 40 meshes with boththe fourth gear rack 38 and the first gear rack 35. The second gearwheels 41 mesh with both the second gear rack 36 and the third gear rack37.

The first gear rack 35 may be referred to as the “housing gear rack”.

The second gear rack 36 may be referred to as the “variable dose rack”.

The third gear rack 37 may be referred to as the “fixed dose rack”

The fourth gear rack 38 may be referred to as the “dosing rack”.

The first wheel 40 may be referred to as the “dosing gear”.

The second wheels 41 may be referred to as the “variable dose/fixed dosegear”.

The interaction of the linear differential gear mechanism components arenow described with respect to FIG. 3. The secondary drive sleeve 24 isconnected to the third gear rack 37 via an engagement section 43 where aprojection of the third gear rack 37 engages a recess in the secondarydrive sleeve 24 such that the third gear rack 37 and the secondary drivesleeve 24 are axially constrained. The primary number sleeve 17 has aproximal flange-like engagement section 44, which urges the sleevesection 42 of the second gear rack 36 in proximal direction during dosesetting.

When a fixed dose is not set be the delivered, the secondary drivesleeve 24 is not actuated and does not displace in proximal direction.The third gear rack 37 remains stationary. Setting a dose of the primarymedicament by operating the dose dial grip 22 results in displacement ofthe number sleeve 17 and in displacement of the second gear rack 36 inproximal direction. As the second gear rack 36 moves in proximaldirection 6, the first gear wheel 40 and the second gear wheel 41 meshwith the associated gear rack. The axial motion of the fourth gear rack38 is the same axial displacement of the second gear rack 36 so that thefourth gear rack 38 and the second gear rack 36 move together inproximal direction. When a set dose of the primary medicament isinjected, the primary number sleeve 17 moves back in distal direction 7thereby moving the fourth gear rack 38 and the second gear rack 36 backto their initial, so called “at rest” position.

If a fixed dose is set to be delivered, the secondary drive sleeve 24and the third gear rack 37 are moved in proximal direction relative tothe first gear rack 35 and the primary number sleeve 17. Axial motion ofthe third gear rack 37 causes rotation of the gear wheel 41 and axialmovement of the transmission element 39. As a result there is relativeaxial motion between the second gear rack 36 and the fourth gear rack38, which is equal to the axial motion of the secondary sleeve 24.

FIG. 4 shows a detailed view of the proximal end of the drug deliverydevice after a dose in the secondary drug delivery assembly has beenset. The button 33 is arranged movable with respect to the dial grip 22and can move relative to the dial grip 22 between the proximal positionas shown in FIG. 4 and a distal position, in which a distal surface ofthe button 33 engages a proximal surface of the dial element 22. Duringthe setting of a fixed dose, the relative axial motion between thefourth gear rack 38 and the second gear 36 rack results in the fourthgear rack 38 abutting the button 33 and displacing the button 33relative to the dial grip 22 in proximal direction such that the button33 protrudes proximally from the dial grip 22 as displayed in FIG. 4.

When the button 33 extends above the dial grip 22, it is indicated thata dose in the secondary drug delivery assembly has been set. Setting ofa variable dose can continue through rotation of the dial grip 22 alongits helical path which causes the dial grip 22 to move in proximaldirection. As the primary number sleeve 17 is displaced helically, thesecond gear rack 36 is moved in proximal direction. The differentialgear mechanism transfers the same axial motion to the fourth gear rack38 such that the second gear rack 36 and the fourth gear rack 38 moveaxially together. The relative position between the second gear rack 36and the fourth gear rack 38 remains constant during the setting of theprimary dose of medicament. Due to the abutment between the fourth gearrack 36 and the button 33 and the contact between the first gear wheel40 and the first gear rack 35, the extension of the button 33 relativeto the dial grip 22 is maintained as both components move away from thehousing.

When the doses of the primary medicament and the secondary medicamentare to be dispensed, the user presses against the proximal face of thebutton 33. As the button 33 is in an engagement with the fourth gearrack 38, this displacement of the button 33 in distal direction forcesthe fourth gear rack 38 in the same. The axial motion is transferred viathe differential gear mechanism to the third gear rack 37. The forceapplied to the second gear rack 36 is reacted by the number sleeve 17,which resists axial motion due to an interlock clutch (not shown)between the number sleeve 17 and the dial grip 22. The force applied tothe third gear rack 37 is transferred to the secondary drive sleeve 24such that a fixed dose is dispensed. During dispense of the fixed dose,the button 33 enters back into the dial grip 22. When the button 33 isback in its proximal position, the user force is transferred directly tothe dial grip 22 so that dispense of the variable dose of the secondmedicament begins. Thereby, it is ensured that the set fixed dose ofmedicament is dispensed prior to the dispense of the variable dose.

During dispensing of the fixed dose, the secondary drive sleeve 24 andthe third gear rack 37 displace axially to their initial position. Asthe third gear rack 37 moves axially and the second gear rack 38 remainsstationary, the fourth gear rack 38 and the button 33 move relative tothe second gear rack 36 and the dial grip 22 until abutment occursbetween the button 33 and the dial grip 22. At this point, the fixeddose is fully dispensed and dispensing of the variable dose can continuewith the user force being transferred from the button directly to thedial grip 22. During dispense of the variable dose, the number sleeve 17winds back into the housing 2 in distal direction along its helicalpath.

When the button 33 is not extended, the user force is transferreddirectly to the dial grip 22 and the primary drive sleeve 18 so that theprimary medicament is dispensed as described above. The dial grip 22 andthe button 33 move axially in distal direction and the second gear rack36 and the fourth gear rack 38 move axially until the dispensing hasbeen completed. The third gear rack 37 remains stationary.

FIG. 5 shows the dose scale on the number sleeve 17 of the primary drugdelivery assembly, which is viewable by the user through a window in thehousing. When a variable dose of the primary medicament is dialed, thenumber sleeve 17 moves along a helical path relative to the housing andthe dialed dose is displayed through the window. Two separate dosescales 46, 47 are marked helically on the surface of number sleeve 17 ina parallel relationship. The first dose scale 45 represents the set doseif no fixed dose in the secondary drug delivery assembly is set. Thesecond dose scale 46 represents the set dose as a combination of adialed variable dose and a fixed dose, resp. a combination of a set dosein the primary drug delivery assembly and a set dose in the secondarydrug delivery assembly. In this embodiment, the second dose scale 46represents an additional 5 units of the parallel first dose scale 45,such that for a given number sleeve position the dose marked onto thesecond dose scale 46 is 5 units greater than that marked onto the firstdose scale 45.

An elongated window (not shown) is provided in the drug delivery devicehousing through which both dose scales 45, 46 are visible. A maskingwindow 47 (FIG. 6) is incorporated into the third gear rack 37, suchthat one of the dose scales 45, 46 is obscured from view depending onthe axial position of the third gear rack 37. During setting of a fixeddose, the third gear rack 37 is moved in proximal direction relative tothe number sleeve 17 as explained above. The masking window 47 displacesin proximal direction, thereby hiding the respective dose unit on firstdose scale 45 (e.g. 2 units) and giving view to respective combined doseon the second dose scale 46 (e.g. 7 units). In the meantime, the button33 projects from the dial grip 22 as explained above.

If a fixed dose has been set, the fixed dose will be dispensed prior tothe variable when the button 33 is pressed. The third gear rack 37 movesrelative to the housing in distal direction, while the number sleeve 17remains stationary. The marking window 47 moves from the second dosescale 46 to the first dose scale 45 during delivery of the fixed dose.After the fixed dose has been delivered, the first dose scale 45 isvisible to the user and as the variable dose is delivered, the displayeddose will reduce due to rotation of the number sleeve 17 along itshelical path.

FIG. 7 displays a fixed dose selection mechanism to enable the user toselect whether or not the fixed dose medicament (the secondarymedicament) will be dispensed along with the variable dose.

The mechanism is configured such that if a user selects to dispense adose of the secondary medicament, resp. the fixed dose liquidmedicament, the secondary dose setting and dose dispensing mechanism isautomatically set to deliver the fixed dose medicament and apredetermined number of units of variable dose liquid medicament. In theembodiment explained below, the predetermined number of units is 5units. The fixed dose selection mechanism includes a selection switch48, a clutch 49, a latch lever 50, a spring 51, a first advance lever 52and a second advance lever 53. These elements interact with the primarynumber sleeve 17, the secondary drive sleeve 24 and the housing 2 asexplained in the following.

As shown in FIG. 8, the clutch 49 comprises a sleeve-like main section54. Reference numerals 6 and 7 are included to indicate proximal anddistal direction when the components are assembled in the drug deliverydevice. The proximal end 6 of the clutch 49 has a smaller outer diameterthan the main section 54 and is provided with a splined outer surface 55with splines extending in axial direction. The distal end 7 of theclutch 49 has engagement arms 56 in a circular formation around alongitudinal axis 57 of the clutch 49 and extending in axial directiontowards the secondary drive sleeve 24. The main section 54 is hollowsuch that the proximal end of the drive sleeve 24 is insertable into themain section 54.

The proximal end section of the secondary drive sleeve 24 is providedwith a number of axially extending grooves 58 that are open at theproximal end such that the radially inner surface of the engagement arms56 may enter the groove. The radially inner surface of the engagementarms 56 and the grooves 58 form a groove/nut or splined connection bywhich rotational movement may be transferred between the clutch 49 andthe secondary drive sleeve 24, while allowing relative axial movement.

On the outer surface of the main section 54, a pin 59 is formed. The pin59 forms an interface with a groove 60 on the inside of the fixed dosemechanism housing 25 as shown in FIG. 9. The groove 60 has two sectionsextending in circumferential direction of the fixed dose mechanismhousing 25, wherein the first section 61 is separated from a secondsection 62 by a sloped or inclined transition 63. Towards the proximalend 6, the first section 61 is set back with respect to the secondsection 62. The pin 59 can run or slide in the groove 60 from the firstsection 61 into the second section 62 via the transition 63 and back.Travel of the pin 59 between the sections 61 and 62 causes the clutch 49to move in axial direction. This interface between the clutch 49 and thefixed dose mechanism housing 25 controls the axial position of theclutch 49 when the clutch 49 is rotated about the longitudinal axis 57.As also obvious from FIG. 9, the fixed dose mechanism housing 25 hasprojections 64 that engage a recess 65 in the housing 2 of the drugdelivery device to ensure the fixated position of fixed dose mechanismhousing 25.

The sleeve-like selection switch 48 is supported rotatable in the drugdelivery housing 2 and may rotate around the longitudinal axis 57. Theclutch 49 is rotationally constrained to the rotation of the selectionswitch 48 via the splined surface 55, which engages a correspondinglyformed inner surface of the selection switch 48 in a splined hole toform a splined interface that allows relative axial movement butprevents relative rotational movement between the clutch 49 and theselection switch 48. The selection switch 48 has a lever surface (notshown) that extends in radial direction through an opening (not shown)in the drug delivery housing 2. The opening is formed such that a usercan actuate the lever and rotate the selection switch around thelongitudinal axis 57.

The selection switch 48 is rotatable between three positions. The firstposition is an intermediate “at rest” or central position. In thisposition, the clutch 49 is in a rotational position relative to the pin59 as shown in FIG. 9. From the “at rest” position, the user rotates theselection switch to set the device to deliver a fixed dose of thesecondary medicament in combination with a variable dose of the primarymedicament or a variable dose of the primary medicament only.

When the selection switch 48 is rotated from the intermediate “at rest”position in clockwise direction when viewed from the proximal end 6, therotation is transferred to the clutch 49 and the pin 59 moves towardsthe right end in the first section 61 into a second position. The clutch49 maintains its axial position. This actuation corresponds to thesituation in which the user selects to set and inject a dose of thesecondary medicament. This position of the selection switch 48 may bereferred to a “fixed dose on” position. Rotation of the clutch 49 istransferred to the secondary drive sleeve 24 which rises towards theclutch 49 in a helical movement. If the selection switch 48 is rotatedback to the central position, the clutch 49 and secondary drive sleeverotate in the same direction and the secondary drive sleeve 24 returnsalong its helical path to unset the set dose. The groove 60 also definesa range, in which the selection switch can be rotated. The maximum valueof rotational movement of the selection switch 48, the clutch 49 and thedrive sleeve is limited.

When the selection switch 48 is rotated from the intermediate “at rest”position in counterclockwise direction when viewed from the proximal end6, the pin 59 engages the intermediate section 63 and enters the secondsection 62 and moves toward the left end of the second section 62 into athird position. This actuation corresponds to the situation in which theuser selects not to set and inject a dose of the secondary medicament.This position of the selection switch 48 may be referred to a “fixeddose off” position. The clutch 49 moves axially towards the selectionswitch 48 due to the inclined intermediate surface and away from thedrive sleeve 24 such that the arms disengage from the grooves 58 (FIG.8) and rotation of the clutch 49 is not transferred to the drive sleeve24.

During dispense of the fixed dose after setting the selection switch 48in the “fixed dose on” position, axial movement of the third gear rackis transferred to the secondary drive sleeve 24, which moves in distaldirection. Due to the splined engagement between the engagement arms 56of the clutch 49 and the grooves 60 of the secondary drive sleeve 24,the selection switch 48 and the clutch 49 remain stationary in axialdirection during dispense of a dose of the secondary medicament.

As shown in FIG. 8, at the proximal end of the grooves 58, a ratchetelement 66 is provided, which engages the engagement arms 56 of theclutch and allows relative rotation between the clutch 49 and thesecondary drive sleeve 24 in a first direction and prevents relativerotation in the opposite direction. This ratchet interface enables theclutch 49 to rotate back to its central “at rest” position withoutcausing a rotation of the secondary drive sleeve 24. Further, when theselection switch 48 is moved from its “at rest position” into the “fixeddose off” position, rotation of the clutch 49 is not transferred to thesecondary drive sleeve, as the engagement arms 56 merely engage theratchet element 66 and rotation of the clutch 49 cannot be transferredthough the ratchet interface.

In FIG. 10, a sectional view of the drug delivery device from theproximal side end in longitudinal direction is presented. The firstadvance lever 52 is support by a pin 67 formed on the housing 2 so thatthe first advance lever 52 can pivot or swivel about an axis runningthough the pin 67 in viewing direction. The second advance lever 53 issupport by a pin 68 formed on the housing 2 so that the second advancelever 53 can pivot or swivel about an axis running though the pin 68 inviewing direction.

The first advance lever 52 is a basically u-shaped element with legsconnected by an intermediate section. A first leg has is provided with afirst engagement section 69 formed as a projection for engagement with acounter projection resp. a first abutment surface 70 formed on the outersurface of the number sleeve 17. The first leg further ends in a secondengagement section 71 formed as a projection for engagement with acounter engagement section 72 formed on the inside of the housing 2. Thesecond leg is provided with an opening to receive the pin 67 and ends inthird engagement section 73 for engagement with a second abutmentsurface 74 formed as a raised boss on the outer surface of the numbersleeve 17.

The second advance lever 53 is a t-shaped element with a first sectionthat has at its end an opening to receive the pin 68. The first sectionends in a second section that runs substantially perpendicular to thefirst section. A first projection 75 engages the first advance lever 52such that the first advance lever 52 swivels or articulates around thepin 67 in clockwise direction when the second advance lever 53 rotatesor swivels around the pin 68 in clockwise direction.

Opposite the first projection 75 lies a second projection 76 forengagement with a first abutment surface 77 formed on the selectionswitch 48, which is shown in FIG. 10 in its “at rest” or centralrotational position. Rotation of the selection switch 48 in clockwisedirection causes the first abutment surface 77 to engage the secondprojection 76. As a result, the second advance lever 53 articulatesabout the pin 68 and the first projection 75 on the second advance lever53 moves the first advance lever 52 around the pin 67 in clockwisedirection. A second abutment surface 78 is provided on the selectionswitch 48 for engagement with a fourth engagement section 79 on thefirst advance lever 52. Rotation of the selection switch 48 incounter-clockwise direction causes the second abutment surface 77 toengage the fourth engagement section 79. As a result, the first advancelever 52 articulates about the pin 67 in clockwise direction.Irrespective of whether the selection switch 48 is rotated clockwise orcounter-clockwise, the first advance lever 52 swings in the clockwisedirection. The spring 51 is located on a pivot within the housing, andprovides a restoring force to return the selection switch 48 to itscentralized ‘at rest’ position.

As shown in FIG. 10, the selection switch 48 is in its “at restposition”. The distance in rotational direction between the raised boss74 and the third engagement section 73 is such that the number sleeve 17can be rotated about a predetermined angular range in clockwisedirection. In the described embodiment this angular range corresponds to2 set units of the primary medicament. When the selection switch is atits “at rest” position, the settable dose in the primary drug deliveryassembly is limited to 2 units. The dial grip 22 may only be rotated upto 2 units in clockwise direction. When the dial grip is rotated to 2units, the boss 74 abuts the third engagement section 73 and preventsfurther rotation of the number sleeve 17 until the first advance lever52 is displaced through activation of the selection switch 48 such thatthe third engagement section 73 is moved away from the boss 74. Thismechanism limits a settable dose of the primary medicament to 2 units,which then can be dispensed by depressing the button 33. If the userwishes to dispense a larger variable dose they must activate theselection switch 48.

Rotation of the selection switch 48 (“fixed dose on”) in clockwisedirection causes the levers 52, 53 to articulate. Simultaneously, theclutch 49 and the secondary drive sleeve 24 are operated and a dose ofthe secondary medicament is set. The second lever 53 causes the firstlever 52 to rotate about the pin 67 so that the third engagement section73 swings away from the number sleeve 17 and the boss 74 so that thelock between the housing and the number sleeve 17 is removed, allowingthe user to continue to dial a variable dose beyond the 2 units limit.

The user may choose to activate the selection switch 48 prior to dialingthe dose in the primary drug delivery assembly. With regard to FIGS. 11ato 11c , when the selection switch 48 is rotated into its “fixed doseon” state prior to rotation of the dial grip, the first engagementsection 69 engages the first abutment surface 70 on number sleeve 17causing the number sleeve 17 to rotate in correspondence to 2 units(FIGS. 11a and 11b ). The first advance lever 52 articulates inclockwise direction until the second engagement section 71 engages theabutment surface 72 on the housing 2 which causes the first engagementsection 69 to move away from the number sleeve 17 at the end of thearticulation. The dose of primary medicament that is dialed with thenumber sleeve 17 corresponds to 2 units. This situation is shown in FIG.11c . Articulation of the first advance lever also moves the thirdengagement section 73 away from the number sleeve 17 so that the user isfree to dial beyond the 2 units limit of the primary medicament byrotating the dose dial grip. Rotation of selection switch 48 into the“fixed dose on” position is transferred to the clutch 49 as describedabove and is transferred to the secondary drive sleeve 24 to set a doseof the secondary medicament.

FIG. 12 shows the situation, in which the user chooses not to set andinject a dose of the secondary medicament. The selection switch 48 isrotated from its central “at rest position” in counterclockwisedirection to its “fixed dose off” state. Rotation of the selectionswitch in counterclockwise direction causes the clutch 49 to rotate incounter-clockwise direction and to move in proximal direction (see FIG.8). The secondary drive sleeve 24 remains stationary due the ratchet 66on the drive sleeve 24 and the axial displacement of the clutch 49. Adose of the secondary medicament is not set. During rotation of theselection switch 48 to the left, the first advance lever 52 is pivotedabout the pin 67 by engagement of the second abutment surface 78 onselection switch 48 with the fourth engagement section 79 on the firstadvance lever 52. 2 units of the primary medicament are set and furtherdialing of the number sleeve 17 is allowed.

The advance levers 52, 53 are held in their articulated position bytheir abutments with the selection switch 48. In this embodiment thelevers 52, 53 act against sprung pivots, such that they return to their‘at rest’ position as shown in FIG. 10 when the selection switch 48returns to its central position. The levers 52, 53 may be accommodatedin the housing in a prestressed condition such that the levers 52, 53tend to return back to their “at rest” state. Alternatively, the levers52, 53 may be formed elastically and mounted in the drug delivery devicein prestressed condition wherein the prestress forces tend to urge thelevers 52, 53 into their “at rest” position.

As shown in FIG. 13, the selection switch 48 is held in the “fixed doseon” or fixed dose off” position by the latch lever 50. The latch lever50 is provided to restrain the selection switch 48 in its set position,until the latch lever 50 is articulated by the number sleeve 17. Thenumber sleeve 17 is provided with a ramp feature 80 on its outersurface, whose outer surface moves away from the axis of rotation of thenumber sleeve 17 in circumferential direction. The latch lever 50 ispivotably support in the housing 2 and can pivot around a pivot point 81around an axis running parallel to the rotational axis of the numbersleeve 17. The latch lever 50 comprises two legs extending from thepivot point in different directions. A first engagement section 82 isprovided for engagement with the ramp 80 and a projection 83 formed as alatch is provided on the other leg for engagement with either a firstslot 84 or a second slot 85 each provided on the selection switch 48,depending on the direction the selection switch 48 is rotated from the“at rest” position. When the selection switch 48 is rotated in clockwisedirection, the projection 83 engages the first slot 84. When theselection switch 48 is rotated in counterclockwise direction, theprojection 83 engages the second slot 85.

When the number sleeve 17 is at a “at rest” position as shown in FIG. 13and the number sleeve 17 has not been rotated to set a dose, the rampfeature 80 acts on the engagement section 82 and urges the projection 83away from the selection switch 48. When the number sleeve 17 is rotatedin clockwise direction, the abutment between the ramp 80 and theengagement section 82 is removed as shown in FIG. 14. The latch lever 50rotates about its sprung pivot point 81 in counterclockwise direction.If the selection switch 48 has not been activated by the user, the latch83 abuts the outer cylindrical surface of the selection switch 48.

When the selection switch 48 is operated, e.g. by moving the selectionswitch into the “fixed dose on” state as shown in FIG. 14, the latch 83engages with the first slot 84, which enables the latch lever 50 tofully rotate about its sprung pivot point 81. The engagement between thelatch lever 50 and the selection switch 48 restrains the selectionswitch 48 in its set position. If the selection switch 48 is moved intothe “fixed dose off” state, the latch 83 engages with the second slot 85and the engagement between the latch lever 50 and the selection switch48 restrains the selection switch 48 in its “fixed dose off” position.

The selection switch 48 remains in its set position until the latchlever 50 is articulated by the abutment with the ramp 80 of the numbersleeve 17. During dispense, the number sleeve 17 rotates backward indistal direction and rotates in counterclockwise direction. At the endof the return movement of the number sleeve 17, the ramp 80 engages theengagement section 82 and the removes the engagement between the latch83 and he selection switch 48. The selection switch 48 returns to its‘at rest’ position under the action of the spring 51 (FIG. 12).

The latch lever 50 is preferably accommodated in the housing in aprestressed condition such that the latch lever 50 tends to pivotagainst the selection switch 48. Alternatively, the latch lever 50 maybe formed elastically and mounted in the housing of the drug deliverydevice in a prestressed condition wherein the prestress force tends tourge the latch lever 50 against the selection switch about the pivotpoint 81.

The embodiment in FIG. 14 also shows possible constructive measureswhich enable to define the value of the fixed dose that can be set withthe secondary drug delivery assembly. On the outer surface of theselection switch 48, a selection bar 86 is provided. The selection bar86 is aligned such that it extends in axial direction 57 as also shownin FIG. 9. The maximum value of rotational movement of the selectionswitch 48 from the “at rest” position in clockwise direction as well asin counterclockwise direction is limited by the selection bar 86engaging abutment surfaces 87 and 88 on the housing 2.

In FIG. 15, the housing 2 of the drug delivery device 1 is split intotwo separable components, a main housing 89 and a second housing, whichin this case is the fixed dose mechanism housing 25. The main housing 89contains the variable dose setting and dose dispense mechanism, theselection switch assembly and the differential gear mechanism, exceptfor the first gear rack 35, which is provided on the fixed dosemechanism housing 25. The fixed dose mechanism housing 25 contains thefixed dose setting and dispense mechanism and the clutch only.

As shown in FIGS. 16a and 16b , a separable interface is providedbetween the third gear rack and the secondary drive sleeve in the fixeddose mechanism housing 25 for axial fixation. Arms 90 (FIG. 16b ) extendfrom the third gear rack. When the fixed dose mechanism housing 25 isattached to the main housing 89, the arms 90 engage through an aperture91 (FIG. 16a ) into a circumferential recess 92 or collar on the outersurface of the drive sleeve 24 such that that the secondary drive sleeve24 is axially constrained to the third gear rack 37. A separableinterface is provided between the selection switch 48 and the clutch 49.The splined outer surface 55 of the clutch 49 is insertable into asplined hole 93 of the selection switch 48. This interface provides arotational constraint between these components, but allows for relativeaxial movement.

The fixed dose mechanism housing 25 can be attached to the main housing89 by latching clips or the like. Releasable connections enable the asub-assembly relating to a single cartridge, to be discarded andreplaced when that cartridge is expended.

REFERENCE NUMERALS

-   -   1 drug delivery device    -   2 housing    -   3 primary drug delivery assembly    -   4 secondary drug delivery assembly    -   5 longitudinal axis of housing    -   6 proximal end    -   7 distal end    -   8 primary reservoir (medicament cartridge)    -   9 secondary reservoir (medicament cartridge)    -   10 septum    -   11 primary medicament    -   12 secondary medicament    -   13 bung    -   14 bung    -   15 variable dose setting and dispense mechanism    -   16 fixed dose setting and dispense mechanism    -   17 number sleeve    -   18 primary drive sleeve    -   19 primary lead screw    -   20 inner body    -   21 primary last dose nut    -   22 dial grips (actuation element)    -   23 secondary lead screw    -   24 secondary drive sleeve    -   25 fixed dose mechanism housing    -   26 differential gear mechanism    -   27 outer surface    -   28 thread    -   29 thread    -   30 inner thread    -   31 bearing    -   32 thread    -   33 button (movable element)    -   34 thread    -   35 first toothing (fixed dose mechanism housing rack)    -   36 second toothing (second gear rack/variable dose rack)    -   37 third toothing (third gear rack/fixed dose rack)    -   38 fourth toothing (fourth gear rack/dosing rack)    -   39 transmission element    -   40 first gear wheel (“dose gear”)    -   41 second gear wheel (“variable dose/fixed dose gear”)    -   42 sleeve element    -   43 engagement section    -   44 flange-like section    -   45 first dose scale    -   46 second dose scale    -   47 masking window    -   48 selection switch    -   49 clutch    -   50 latch lever    -   51 spring    -   52 first advance lever    -   53 second advance lever    -   54 main section    -   55 splined surface    -   56 engagement arms    -   57 longitudinal axis    -   58 grooves    -   59 pin    -   60 groove    -   61 first section    -   62 second section    -   63 transition    -   64 projection    -   65 recess    -   66 ratchet    -   67 pin    -   68 pin    -   69 first engagement section    -   70 first abutment surface on number sleeve    -   71 second engagement section    -   72 abutment surface of housing    -   73 third engagement section    -   74 second abutment surface on number sleeve (raised boss)    -   75 first projection    -   76 second projection    -   77 first abutment surface on selection switch    -   78 second abutment surface on selection switch    -   79 fourth engagement section    -   80 ramp feature on number sleeve    -   81 pivot point    -   82 engagement section on latch lever    -   83 projection on latch lever (latch)    -   84 first slot    -   85 second slot    -   86 selection bar    -   87 abutment surface    -   88 abutment surface    -   89 main housing    -   90 arms    -   91 aperture    -   92 circumferential recess (collar)    -   93 splined hole

1. Differential gear mechanism (26) for a drug delivery device with aprimary drug delivery assembly (3) comprising a primary dose dial sleeve(17) and with a secondary drug delivery assembly (4) comprising asecondary drive sleeve (24); the differential gear mechanism (26)comprising: a first toothing (35); a transmission element (39) movablerelative to the first toothing (35) in a first axial direction andcomprising at least one first gear wheel (40) and at least one secondgear wheel (41) concentrically arranged with respect to the first gearwheel (40); a second toothing (36) configured to be axially constrainedto the primary dose dial sleeve (17); a third toothing (37) configuredto be axially constrained to the secondary drive sleeve (24); a fourthtoothing (38); wherein the second toothing (36), the third toothing (37)and the fourth toothing (38) are moveable relative to the first toothing(35) in the first axial direction; wherein the first gear wheel (40) isin meshed engagement with the first toothing (35) and the fourthtoothing (38); and wherein the second gear wheel (41) is in meshedengagement with the second toothing (36) and third toothing (37) 2.Differential gear mechanism according to claim 1, wherein the fourthtoothing (38) is movable relative to the second toothing (36) in theaxial direction.
 3. Differential gear mechanism according to any of theclaim 1 or 2, wherein each of the toothings (35, 36, 37, 38) is formedas a gear rack.
 4. Differential gear mechanism (26) for a drug deliverydevice with a primary drug delivery assembly (3) comprising a primarydose dial sleeve (17) configured to move proximally in a helicalmovement during setting of a dose of a primary medicament (11) containedin a primary reservoir (8) of the primary drug delivery assembly (3) andwith a secondary drug delivery assembly (4) comprising a secondary drivesleeve (24) configured to move in a proximal direction in a helicalmovement during setting of a dose of a secondary medicament (12)contained in a secondary reservoir (9) of the secondary drug deliveryassembly (4); the differential gear mechanism (26) comprising: a firsttoothing (35); a transmission element (39) movable relative to the firsttoothing (35) in a first axial direction and comprising at least onefirst gear wheel (40) and at least one second gear wheel (41)concentrically arranged with respect to the first gear wheel (40); asecond toothing (36) axially constrained to the primary dose dial sleeve(17); a third toothing (37) axially constrained to the secondary drivesleeve (24); a fourth toothing (38); wherein the second toothing (36),the third toothing (37) and the fourth toothing (38) are moveablerelative to the first toothing (35) in the first axial direction andwherein the fourth toothing (38) is movable relative to the secondtoothing (36) in the axial direction; wherein the first gear wheel (40)is in meshed engagement with the first toothing (35) and the fourthtoothing (38); and wherein the second gear wheel (41) is in meshedengagement with the second toothing (36) and third toothing (37), suchthat when the secondary drive sleeve (24) moves proximally, axial motionof the third toothing (37) causes relative axial movement between thesecond toothing (36) and the fourth toothing (38), and such that whenthe primary dose dial sleeve (17) moves proximally motion of the secondtoothing (36) in proximal direction causes the second toothing (36) andthe forth toothing (38) to move together in proximal direction.
 5. Drugdelivery device comprising a primary drug delivery assembly (3) with aprimary dose dial sleeve (17) and a secondary drug delivery assembly (4)with a secondary drive sleeve (24), and a differential gear mechanism(26) according to any of the preceding claims, wherein the firsttoothing (35) is fixed stationary with respect to a drug deliveryhousing (2), wherein the second toothing (36) is axially constrained tothe primary dose dial sleeve (17), and wherein the third toothing (37)is axially constrained to the secondary drive sleeve (24).
 6. Drugdelivery device according to claim 5 further comprising a movableelement (30) movable with respect to the primary dose dial sleeve (17)between a first position and a second position, wherein the fourthtoothing (38) is arranged to move the moveable element (33) from thefirst into the second position during dose setting of the secondary drugdelivery assembly (4).
 7. Drug delivery device according to claim 6,wherein the movable element (33) is configured to move the fourthtoothing (38) in distal direction when moved from the second positioninto the first position.
 8. Drug delivery device according any of theclaims 5 to 7, wherein the primary dose dial sleeve (17) is configuredto move proximally in a helical movement during dose setting and to movedistally in a helical movement during dose dispense, wherein anactuation element (22) is axially constrained to the second toothing(36).
 9. Drug delivery device according to claim 8, wherein theactuation element (22) accommodates at least partly the movable element(33).
 10. Drug delivery device according to any of the claims 8 to 9,wherein the movable element (33) is moveable relative to the actuationelement (22) in axial direction, wherein when the movable element (33)is moved from its second position to its first position, the movableelement (33) engages the actuation element (22) such that furthermovement of the moveable element (33) in distal direction is transferredto the actuation element (22).
 11. Drug delivery device according to anyof the claims 5 to 10, wherein the primary dose dial sleeve is a numbersleeve (17) with indices for indicating the value of a set dose
 12. Drugdelivery device according to any of the claims to 11, wherein themovable element (33) is a dispense button.
 13. Drug delivery deviceaccording to any of the claims 5 to 12, wherein the actuation element(22) is a dose dial element.
 14. Drug delivery device according to anyof the claims 5 to 13, wherein the primary drug delivery assembly (3)comprises a variable dose setting mechanism and wherein the secondarydrug delivery assembly (4) comprises a fixed dose setting mechanism. 15.Drug delivery device according to any of the claims 5 to 14, wherein theprimary drug delivery assembly (3) accommodates a primary medicament(11) and wherein the secondary drug delivery assembly (4) accommodates asecondary medicament (12).